Cita Bauer1, Julia Kaiser1, Jelena Sikimic1, Peter Krippeit-Drews1, Martina Düfer2, Gisela Drews3. 1. Department of Pharmacology, Institute of Pharmacy, University of Tübingen, Auf der Morgenstelle 8, Tübingen, D-72076, Germany. 2. Department of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstraße 48, Münster, D-48149, Germany. 3. Department of Pharmacology, Institute of Pharmacy, University of Tübingen, Auf der Morgenstelle 8, Tübingen, D-72076, Germany. gisela.drews@uni-tuebingen.de.
Abstract
PURPOSE: The role of ATP, which is secreted by pancreatic β-cells, is still a matter of debate. It has been postulated that extracellular ATP acts as a positive auto- or paracrine signal in β-cells amplifying insulin secretion. However, there is rising evidence that extracellular ATP may also mediate a negative signal. METHODS: We evaluated whether extracellular ATP interferes with the Ca2+-mediated negative feedback mechanism that regulates oscillatory activity of β-cells. RESULTS: To experimentally uncover the Ca2+-induced feedback we applied a high extracellular Ca2+ concentration. Under this condition ATP (100 µM) inhibited glucose-evoked oscillations of electrical activity and hyperpolarized the membrane potential. Furthermore, ATP acutely increased the interburst phase of Ca2+ oscillations and reduced the current through L-type Ca2+ channels. Accordingly, ATP (500 µM) decreased glucose-induced insulin secretion. The ATP effect was not mimicked by AMP, ADP, or adenosine. The use of specific agonists and antagonists and mice deficient of large conductance Ca2+-dependent K+ channels revealed that P2X, but not P2Y receptors, and Ca2+-dependent K+ channels are involved in the underlying signaling cascade induced by ATP. The effectiveness of ATP to interfere with parameters of stimulus-secretion coupling is markedly reduced at low extracellular Ca2+ concentration. CONCLUSION: It is suggested that extracellular ATP which is co-secreted with insulin in a pulsatile manner during glucose-stimulated exocytosis provides a negative feedback signal driving β-cell oscillations in co-operation with Ca2+ and other signals.
PURPOSE: The role of ATP, which is secreted by pancreatic β-cells, is still a matter of debate. It has been postulated that extracellular ATP acts as a positive auto- or paracrine signal in β-cells amplifying insulin secretion. However, there is rising evidence that extracellular ATP may also mediate a negative signal. METHODS: We evaluated whether extracellular ATP interferes with the Ca2+-mediated negative feedback mechanism that regulates oscillatory activity of β-cells. RESULTS: To experimentally uncover the Ca2+-induced feedback we applied a high extracellular Ca2+ concentration. Under this condition ATP (100 µM) inhibited glucose-evoked oscillations of electrical activity and hyperpolarized the membrane potential. Furthermore, ATP acutely increased the interburst phase of Ca2+ oscillations and reduced the current through L-type Ca2+ channels. Accordingly, ATP (500 µM) decreased glucose-induced insulin secretion. The ATP effect was not mimicked by AMP, ADP, or adenosine. The use of specific agonists and antagonists and mice deficient of large conductance Ca2+-dependent K+ channels revealed that P2X, but not P2Y receptors, and Ca2+-dependent K+ channels are involved in the underlying signaling cascade induced by ATP. The effectiveness of ATP to interfere with parameters of stimulus-secretion coupling is markedly reduced at low extracellular Ca2+ concentration. CONCLUSION: It is suggested that extracellular ATP which is co-secreted with insulin in a pulsatile manner during glucose-stimulated exocytosis provides a negative feedback signal driving β-cell oscillations in co-operation with Ca2+ and other signals.
Authors: S Amisten; S Meidute-Abaraviciene; C Tan; B Olde; I Lundquist; A Salehi; D Erlinge Journal: Diabetologia Date: 2010-06-06 Impact factor: 10.122
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